Anti-Angiogenic Therapy: Current Challenges and Future Perspectives

Round 1

Reviewer 1 Report

This is a nice and well written review dealing with the use of anti-angiogenic molecules in cancer/cancer resistance to classical chemotheraputic drugs. I have a few comments that I would like to be taken into account by the authors.

Introduction : « the initial event…. » the sentence is not clear. Either the « initial event » is a genetic condition (germinal mutation associated to cancer susceptibilty, eg : BRCA1/2) or, dealing with sporadic cancers where it is hard to show in human neoplasia « who » is the first in cancer «initiation ».

detail points :

figure 1. I don’t understand where filipodia are ; they canont be seen in the inset. Their main components are poorly described, eventhough this is not the major topic of the review.

figure 2. to help the reader , the several downstream pathways could be illustrated

5.3 : ROS ; the NFR2, HIF1 scavengers or appropriate DNA repair complexes are not mentioned.

Author Response

Reviewer 1
This is a nice and well written review dealing with the use of anti-angiogenic 
molecules in cancer/cancer resistance to classical chemotheraputic drugs. I have 
a few comments that I would like to be taken into account by the authors.
- Thank you very much for your comments and criticisms.
Introduction : « the initial event…. » the sentence is not clear. Either the « initial 
event » is a genetic condition (germinal mutation associated to cancer 
susceptibilty, eg : BRCA1/2) or, dealing with sporadic cancers where it is hard to 
show in human neoplasia « who » is the first in cancer «initiation ».
- We agree. This part of the sentence was removed and the relevance of 
angiogenesis in cancer progression was maintained.
detail points :
figure 1. I don’t understand where filipodia are ; they canont be seen in the inset. 
Their main components are poorly described, eventhough this is not the major 
topic of the review.
- We agree with your suggestion and tip cells morphology was altered in order to 
present filipodia, whose structure is briefly described in the figure legend.
figure 2. to help the reader, the several downstream pathways could be illustrated
- We agree and the main signaling pathways related to the receptors targeted by 
anti-angiogenic drugs were added to figure 2.
5.3 : ROS ; the NFR2, HIF1  scavengers or appropriate DNA repair complexes 
 are not mentioned.
- A new section (5.3) dedicated to the impact of drugs targeting DNA repair in 
cancer angiogenesis, was added. The fact that oxidative stress regulators and 
the generation of free radicals are relevant in mutagenesis and in tumor 
angiogenesis was reinforced.

Reviewer 2 Report

In the following, I would like to comment on the review paper by Ms. Lopes Coelho. The paper deals with the effect of antiangiogenic therapy on the tumor cell and tumor stroma, its limitations in the past and its chance in the future with the combination of immunotherapies. The presented review is very detailed, well structured and with very successful illustrations. 
Subjectively, there is little to improve or suggest for improvement. I would like to see a table with promising ongoing studies on the combination of anti-angiogenesis + immunotherapy. I would like to congratulate the authors for this successful work. 

Author Response

Reviewer 2
In the following, I would like to comment on the review paper by Ms. Lopes Coelho. 
The paper deals with the effect of antiangiogenic therapy on the tumor cell and 
tumor stroma, its limitations in the past and its chance in the future with the 
combination of immunotherapies. The presented review is very detailed, well 
structured and with very successful illustrations.
Subjectively, there is little to improve or suggest for improvement. I would like to 
see a table with promising ongoing studies on the combination of antiangiogenesis + immunotherapy. I would like to congratulate the authors for this 
successful work.
- Thank you very much for your comments.
- Table 1 was added to the manuscript, it presents clinical trials on the combined 
testing of anti-antiangiogenic therapy and immunotherapy